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The Journal of Neuroscience, June 1, 1999, 19(11):4627-4633
The Dopamine D2, but not D3 or
D4, Receptor Subtype is Essential for the Disruption of
Prepulse Inhibition Produced by Amphetamine in Mice
Rebecca J.
Ralph1,
Geoffrey B.
Varty2,
Michele
A.
Kelly3,
Yan-Min
Wang5,
Marc G.
Caron5,
Marcelo
Rubinstein6,
David K.
Grandy4,
Malcolm J.
Low3, and
Mark A.
Geyer1, 2
Departments of 1 Neuroscience and
2 Psychiatry, University of California at San Diego, La
Jolla, California 92093-0804, 3 Vollum Institute and
4 Department of Physiology and Pharmacology, Oregon Health
Sciences University, Portland, Oregon 97201, 5 Howard
Hughes Medical Institute Laboratories, Department of Cell Biology, Duke
University Medical Center, Durham North Carolina 27710, and
6 Instituto de Investigaciones en Ingenieriá
Genética y Biología Molecular, Consejo Nacional de
Investigiones Científicas y Técnicas y Departamento de
Biología, Universidad de Buenos Aires, 1428 Buenos Aires,
Argentina
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ABSTRACT |
Brain dopamine (DA) systems are involved in the modulation of the
sensorimotor gating phenomenon known as prepulse inhibition (PPI). The
class of D2-like receptors, including the D2, D3, and D4 receptor
subtypes, have all been implicated in the control of PPI via studies of
DA agonists and antagonists in rats. Nevertheless, the functional
relevance of each receptor subtype remains unclear because these
ligands are not specific. To determine the relevance of each receptor
subtype, we used genetically altered strains of "knock-out" mice
lacking the DA D2, D3, or D4 receptors. We tested the effects of each
knock-out on both the phenotypic expression of PPI and the disruption
of PPI produced by the indirect DA agonist d-amphetamine
(AMPH). No phenotypic differences in PPI were observed at baseline.
AMPH significantly disrupted PPI in the D2 (+/+) mice but had no effect
in the D2 ( /) mice. After AMPH treatment, both DA D3 and D4
receptor (+/+) and (/) mice had significant disruptions in PPI.
These findings indicate that the AMPH-induced disruption of PPI is
mediated via the DA D2 receptor and not the D3 or D4 receptor subtypes.
Uncovering the neural mechanisms involved in PPI will further our
understanding of the substrates of sensorimotor gating and could lead
to better therapeutics to treat gating disorders, such as schizophrenia.
Key words:
prepulse inhibition; startle; mice; dopamine receptors; genetics; amphetamine
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INTRODUCTION |
Prepulse inhibition (PPI) is a
cross-species measure of a sensorimotor gating phenomenon in which
startle magnitude is reduced when the startling stimulus is preceded by
a low-intensity prepulse. Disruptions in PPI have been reported in
certain psychiatric disorders associated with dopamine (DA)
dysregulation, including schizophrenia (Braff et al., 1992 ). Previous
animal studies have demonstrated a contribution of DA and its receptor
subtypes to the modulation of PPI. Consistent with the DA hypothesis of
schizophrenia, indirect DA agonists, such as amphetamine (AMPH), and
direct DA agonists, such as apomorphine, disrupt PPI in rats (Mansbach
et al., 1988). These apomorphine-induced disruptions of PPI are
prevented by typical and atypical antipsychotics (Mansbach et al.,
1988; Swerdlow et al., 1991; Swerdlow and Geyer, 1993).
Many studies have been conducted in rats using selective DA D2 family
antagonists and agonists to elucidate the involvement of the DA D2, D3,
and/or D4 receptor (D2R, D3R, and D4R, respectively) subtypes in
the modulation of PPI. The D2 receptor was implicated because
apomorphine disrupted PPI, and haloperidol and the D2-like receptor
antagonist raclopride could reverse the apomorphine-induced disruption
of PPI (Mansbach et al., 1988; Swerdlow et al., 1991). Furthermore, the
preferential D2-like receptor agonist quinpirole was shown to disrupt
PPI (Peng et al., 1990). Reports that the D3 agonists 7-OH-DPAT,
PD128907, and quinelorane also disrupted PPI indicated that the D3
receptor might be involved in the modulation of PPI (Caine et al.,
1995; Bristow et al., 1996; Varty and Higgins, 1998), although the
preferential D3 antagonist UH232 failed to restore an
apomorphine-induced disruption of PPI (Caine et al., 1995). Support for
a role of the D4 receptor in the modulation of PPI came from reports
that D4 antagonists, such as CP-293,019, U-101,387, and PD167021,
restored an apomorphine-induced disruption of PPI (Corbin and Heffner,
1997; Mansbach et al., 1998), although conflicting reports of the
efficacy of other selective antagonists followed. L-745,870 was
reported as reversing an apomorphine-induced disruption of PPI
(Mansbach et al., 1998), whereas others found it ineffective (Bristow
et al., 1997a; Corbin and Heffner, 1997). Although it is clear that the
D2 family of receptors is involved in the modulation of PPI, the
specific role of each receptor subtype has remained unclear because
of limitations in the availability of selective ligands.
Recent reports have shown that mice display robust PPI and that DA
agonists disrupt PPI in mice (Dulawa and Geyer, 1996; Paylor and
Crawley, 1997; Bullock et al., 1998). Thus, to overcome the problems of
the lack of selective DA receptor compounds, we used genetically
mutated mice to assess the involvement of the DA D2 family of receptors
in the modulation of PPI. Specifically, we used D2R, D3R, and D4R
mutant mice to determine whether the removal of a specific receptor
subtype would change the normal expression of either the acoustic
startle response (ASR), PPI, or the ability of AMPH to disrupt PPI.
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MATERIALS AND METHODS |
Subjects. D2R and D4R mice were generated at Oregon
Health Sciences University (Portland, OR). The D2R mice (Kelly et al., 1997, 1998) were incipient congenic, having been backcrossed for five
generations (N5) to the inbred C57BL/6J (The Jackson Laboratory, Bar
Harbor, ME) strain of mice. The F2 hybrid D4R mice (Rubinstein et al.,
1997) were a combination of C57BL/6J and 129/Ola genetic backgrounds.
The D3R mutant mice were generated at Duke University Medical Center
(Durham, NC). Initial characterization has indicated no genotypic or
phenotypic differences between this line and the other two previously
reported D3R knock-out (KO) lines (Accili et al., 1996; Xu et
al., 1997). Full characterization of this line will be published
elsewhere (Y.-M. Wang, R. R. Gainetdinov, and M. G. Caron,
unpublished observations). The F2 D3R mice were a crossbreed
between the C57BL/6J and 129 SvJ strains (The Jackson Laboratory). All
mice were allowed to acclimate to the vivarium at University of
California at San Diego (San Diego, CA) for at least 1 week before
behavioral testing in an American Association for Accreditation of
Laboratory Animal Care-approved animal facility. This facility
meets all federal and state requirements for animal care, and federal
and state guidelines for the care and treatment of laboratory animals
are followed. All genotyping of the mice was performed by the home
institutions. The mice were group housed (segregated by sex when
applicable) in a climate-controlled animal colony with a reversed 12 hr
light/dark cycle (lights on at 7:00 P.M., lights off at 7:00
A.M.). All behavioral testing occurred between 9:00 A.M. and 5:00 P.M.
Food (Harlan Teklab, Madison, WI) and water were available throughout
the experiments, except during behavioral testing.
Drugs. d-Amphetamine sulfate (AMPH) was
obtained from Sigma (St. Louis, MO) and was dissolved in 0.9% saline.
Free base drug weights were used in all drug calculations. Injections
of 10.0 mg/kg AMPH or saline were given intraperitoneally
immediately before behavioral testing at a volume of 5 ml/kg body
weight. Data from pilot studies were used to determine that 10 mg/kg
was the optimal dose of AMPH necessary to disrupt PPI in mice (data not shown).
Apparatus. Startle reactivity was measured using four
startle chambers (SR-LAB; San Diego Instruments, San Diego, CA). Each chamber consisted of a clear nonrestrictive Plexiglas cylinder resting
on a platform inside a ventilated box. A high-frequency loudspeaker
inside the chamber produced both a continuous background noise of 65 dB
and the various acoustic stimuli. Vibrations of the Plexiglas cylinder
caused by the whole-body startle response of the animal were transduced
into analog signals by a piezoelectric unit attached to the platform.
These signals were then digitized and stored on a computer. Sixty-five
readings were taken at 1 msec intervals, starting at stimulus onset,
and the average amplitude was used to determine the ASR. Sound levels
in dB(A) sound pressure level were measured as described
previously (Dulawa et al., 1997), and the SR-LAB calibration unit was
used routinely to ensure consistent stabilimeter sensitivity between
test chambers and over time (Geyer and Swerdlow, 1998).
Test sessions. All PPI test sessions consisted of startle
trials (PULSE-ALONE), prepulse trials (PREPULSE+PULSE), and no-stimulus trials (NOSTIM). The PULSE-ALONE trial consisted of a 40 msec, 120 dB
pulse. The PREPULSE+PULSE trials consisted of a 20 msec prepulse, 100 msec delay and then a 40 msec, 120 dB startle pulse (120 msec
onset-to-onset interval). Prepulse intensities were 4, 8, and 16 dB
above the 65 dB background noise. The NOSTIM trial consisted of
background noise only. Each test session began and ended with five
presentations of the PULSE-ALONE trial; in between, each trial type was
presented 10 times in a pseudorandom order. There was an average of 15 sec (range, 12-30 sec) between trials. After the mice were placed in
the startle chambers, a 65 dB background noise level was presented for
a 10 min acclimation period and continued throughout the test session.
Each animal was always tested in the same startle chamber.
Data analyses. The amount of PPI was calculated as a
percentage score for each prepulse trial type: % PPI = 100 {[(startle response for PREPULSE+PULSE)/(startle response for
PULSE-ALONE)] × 100}. Startle magnitude was calculated as the
average response to all of the PULSE-ALONE trials, excluding the first
and last blocks of five PULSE-ALONE trials. Data from the first and
last blocks of PULSE-ALONE trials were analyzed but are not included because they are similar to the startle reactivity data presented. ANOVAs were used to compare means, and where applicable,
Tukey's tests were used for post hoc analysis (see
each experiment description). For brevity, main effects of prepulse
intensity (which were always significant) will not be discussed, and
F values will be reported only when significant. All data
were also analyzed using difference scores, where PPI difference = (PULSE-ALONE PREPULSE+PULSE) for each prepulse trial type.
Using these difference scores, the same ANOVAs were performed, and the
same effect of AMPH on PPI was found in the D2R, D3R, and D4R mice
(data not shown). Data from the NOSTIM trials are not included in
Results because the effects of AMPH were inconsistent and inconclusive.
Response values on the NOSTIM trials were trivial relative to values on
trials containing startle stimuli.
Experiment 1. Nine wild-type (WT) (+/+), 25 heterozygote (+/), and 12 knock-out (/) male and 9 wild-type
(+/+), 12 heterozygote (+/), and 11 knock-out (/) female D2R mice
were characterized in a baseline test session to determine the ASR and
PPI levels. Three days later, mice from each genotype were assigned to
receive either 10.0 mg/kg AMPH or vehicle (balanced for baseline ASR, PPI, startle chamber assignment, and treatment) and were tested in the
PPI session. The mice were placed into the startle chambers immediately
after each injection. The mice were tested again 1 week later,
counterbalanced for drug treatment, to complete a within-subjects
design. The baseline PPI data were analyzed using a three-way ANOVA,
with gender and genotype as between-subjects factors and prepulse
intensity as a within-subjects factor. Startle magnitude was analyzed
using a two-way ANOVA, with gender and genotype as between-subjects
factors. After the administration of AMPH, PPI data were analyzed using
a four-way ANOVA, with gender and genotype as between-subjects factors
and drug treatment and prepulse intensity as within-subjects factors.
In post hoc ANOVAs, the  level was adjusted to
p < 0.025 to accommodate the removal of genotype as a
factor. Startle magnitude was analyzed using a three-way ANOVA, with
drug treatment as a within-subjects factor and gender and genotype as
between-subjects factors.
Experiment 2. Ten wild-type (+/+) and nine knock-out (/)
male D3R mice were characterized initially to establish their baseline ASR and PPI levels. Three days later, mice from each genotype were
assigned to either 10.0 mg/kg AMPH or vehicle treatment groups (balanced for baseline ASR, PPI, startle chamber assignment, and treatment) and tested in a PPI session. The mice were tested again 1 week later, counterbalanced for drug treatment, to complete a
within-subjects design. The same ANOVA structures used in experiment 1 were used to analyze the D3R PPI and startle magnitude data.
Experiment 3. Twenty-eight wild-type (+/+) and 29 knock-out
(/) male and 28 wild-type (+/+) and 29 knock-out (/) female D4R
mice were characterized initially to ascertain their baseline ASR and
PPI levels. Three days later, mice from each genotype were assigned to
test groups (male: WT vehicle, 9; drug, 7; KO vehicle, 10; drug, 9;
female: WT vehicle, 10; drug, 9; KO vehicle, 9; drug, 8) balanced for
baseline startle magnitude, PPI, and startle chamber assignment. Each
animal received an injection of either vehicle or 10 mg/kg AMPH before
being tested. The same ANOVA structures used in experiment 1 were used
to analyze the D4R data, except drug treatment was a between-subjects factor.
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RESULTS |
D2 receptor mice
There were no significant differences between D2R genotypes in the
initial characterization of PPI (Fig.
1A) or the ASR (Table 1), although there was a gender effect on
startle reactivity in which female D2R mice had lower ASR than male D2R
mice (F(1,85) = 7.7; p < 0.01).
Because there was no effect of or interaction with gender in the AMPH
experiment, male and female PPI data were combined. There were main
effects of drug treatment on PPI (F(1,154) = 32.8; p < 0.01) and a drug treatment by genotype
interaction (F(2,154) = 6.4; p < 0.05). Data were segregated by genotype, and two-way ANOVAs were
completed with drug treatment and prepulse intensity as a
within-subjects factors. As expected from previous work (Mansbach et
al., 1988; Dulawa and Geyer, 1996), AMPH reduced PPI significantly in
D2R wild-type (+/+) mice (F(1,17) = 34.7; p < 0.01) (Fig.
2A), and there was a
trend toward a disruption in the heterozygous (+/) mice
(F(1,36) = 4.9; p = 0.03) (Fig. 2B). In contrast, AMPH had no significant effect on
PPI in the knock-out (/) mice (Fig. 2C). There was a
significant main effect of gender on startle reactivity after AMPH
treatment (F(1,74) = 4.6; p < 0.05). Further analyses revealed that there were significant main
effects of AMPH on startle reactivity in both male
(F(1,45) = 23; p < 0.05) and
female (F(1,29) = 19.3; p < 0.01) D2R mice (Table 2). AMPH
significantly reduced startle reactivity in all genotypes in both male
and female D2R mice.
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Figure 1.
Baseline PPI for D2R (A),
D3R (B), and D4R (C)
mutant mice. There were comparable levels of PPI between wild-type
(+/+) (black bars), heterozygous (+/)
(gray bars), and knock-out (/) (white
bars) within each mutant line of mice. Values represent
mean ± SEM percentage of PPI for each prepulse
intensity.
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Figure 2.
PPI for D2R mutant mice with vehicle control
(0.9% saline; open bars) and AMPH (10 mg/kg;
hatched bars). Post hoc ANOVAs revealed
that AMPH significantly reduced PPI at the 4, 8, and 16 dB prepulse
intensities (p < 0.01) in D2R wild-type
(+/+) mice (A) but had no significant
effect in the heterozygote (+/) (B) or
knock-out (/) (C) mice. Values represent
mean ± SEM percentage of PPI for each prepulse intensity.
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D3 receptor mice
There were no differences in either PPI (Fig.
1B) or the ASR (Table 1) between the D3R wild-type
(+/+) and knock-out (/) mice at baseline testing. After AMPH
treatment, there were main effects of drug treatment on both PPI
(F(1,17) = 19.3; p < 0.01) and
startle reactivity (F(1,17) = 9.9;
p < 0.01), but there were no interactions. As in the
baseline test, there were no significant main effects of genotype on
PPI or startle reactivity. AMPH significantly reduced PPI (Fig.
3) and the ASR (Table 2) in both the D3R
wild-type (+/+) and knock-out (/) mice.
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Figure 3.
PPI for D3R mutant mice with vehicle control
(0.9% saline; open bars) and AMPH (10 mg/kg;
hatched bars). After AMPH treatment, both wild-type(+/+)
(A) and knock-out (/)
(B) mice had significantly disrupted PPI
(p < 0.01). Values represent mean ± SEM percentage of PPI for each prepulse intensity.
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D4 receptor mice
In the initial characterization of PPI, there was no main effect
of or interactions with gender; therefore, male and female were
considered together. There was a significant main effect of genotype
(F(1,113) = 7.6; p < 0.01) in
which D4R knock-out (/) mice had higher PPI than wild-type (+/+)
mice (Fig. 1C). There were no significant differences in the
ASR between the D4R wild-type (+/+) and knock-out (/) mice at
baseline testing (Table 2). In the AMPH experiment, female and male D4R
data were considered separately because there was a gender by treatment
interaction on PPI (F(1,63) = 4.6;
p < 0.05). In contrast to the baseline study, there
were no significant main effects of genotype on PPI or startle
reactivity in the AMPH experiment in the female D4R mice. There were,
however, significant main effects of AMPH treatment on PPI
(F(1,32) = 26.3; p < 0.01) and
startle reactivity (F(1,32) = 23.5;
p < 0.01), but there were no interactions between
genotype and treatment. AMPH significantly reduced PPI (Fig.
4A,B)
and startle magnitude (Table 2) in both the D4R wild-type (+/+) and knock-out (/) female mice. As with the female mice, there were no
main effects of genotype on PPI or startle reactivity in the AMPH
experiment with male D4R mice. There was a trend toward a main effect
of treatment on PPI (F(1,31) = 3.5;
p = 0.07), but there were no main effects or
interactions with genotype (Fig. 4C,D). There was
a main effect of AMPH on startle magnitude
(F(1,29) = 32.6; p < 0.01).
Post hoc analyses confirmed that AMPH reduced startle in
both D4R wild-type (+/+) and knock-out (/) mice (Table 2).
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Figure 4.
PPI for male and female D4R mutant mice with
vehicle control (0.9% saline; open bars) and AMPH (10 mg/kg; hatched bars). After AMPH treatment, both female
wild-type (+/+) (A) and knock-out (/)
(B) mice had significantly disrupted PPI
(p < 0.01). In the male D4R mice, however,
there was only a trend (p = 0.07) for AMPH
treatment to disrupt PPI in wild-type (+/+) (C)
and knock-out (/) (D) mice, with no
significant interaction with genotype. Values represent mean ± SEM percentage of PPI for each prepulse intensity.
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DISCUSSION |
We characterized the startle behavior of DA D2R, D3R, and D4R
mutant mice and found that all strains displayed robust PPI and ASR,
regardless of genotype. After AMPH treatment, all groups of mice
exhibited disrupted PPI, except for the mice lacking the DA D2 receptor
subtype. The D2R, D3R, and D4R mice all had significant reductions in
startle reactivity after treatment with AMPH, with the various missing
receptor subtypes having no effect on the ability of AMPH to reduce ASR
in mice. Thus, the D2R subtype of the D2 family of receptors appears to
be critical to the PPI-disruptive effects of an indirect DA agonist,
but the role of the D2R in the effects of the indirect agonist on
startle reactivity remains unclear. Although the lack of AMPH effect in
the D2R knock-out (/) mice might be attributed to the addition of
C57BL/6J genetic material through backcrossing, AMPH was effective in
disrupting PPI in the D2R wild-type (+/+) mice, which have the closest
genetic make-up to the D2R mutant mouse. AMPH also disrupted PPI in
dose response studies of the 129SvEv, 129SvJ, and C57BL/6J strains of
mice (R. J. Ralph and M. A. Geyer, unpublished observations). It
will be necessary, however, to conduct further studies using fully
congenic lines of each of the mutant mice described here (once they are
created) to further verify our results.
In the experiments using the D2R and D4R mice, some gender and genotype
effects were detected on both PPI and ASR. Gender influenced startle
magnitude in the D2R mice both at baseline and after AMPH, but despite
these main effects of gender, the disruptive effect of AMPH on PPI and
the AMPH-induced reduction in startle reactivity were consistent across
genotypes. These findings indicate that the gender effect seen in the
D2R mice is unrelated to the effects of AMPH on PPI or ASR. The D2R
heterozygote (+/) mice reportedly have ~50% of the D2R (Kelly et
al., 1997) and have demonstrated phenotypic responses that were
intermediate to those of the wild-type (+/+) and knock-out (/) mice
when given haloperidol (Kelly et al., 1998). Interestingly, there was a
trend toward an effect of AMPH on PPI in the D2R heterozygote, suggesting a gene dosage effect. As only one dose of AMPH was tested
here, an AMPH dose response might reveal further phenotypic distinctions in the D2R mice. In the D4R mice, the small but
significant main effect of genotype on PPI at baseline testing was not
accompanied by an effect of genotype on startle reactivity. Thus, the
increase in PPI seen in the D4R knock-out mice was not attributable to a difference in ASR between genotypes. This effect was not consistent, however, because there was no significant effect of genotype in the
AMPH experiments in either male or female D4R mice. Similarly, this
phenotypic difference in PPI has not been observed consistently in
other cohorts of D4R mice (S. C. Dulawa and M. A. Geyer, unpublished observations). The gender by treatment
interaction found in the D4R AMPH experiment is consistent with the
observation of a significant AMPH-induced disruption of PPI in the
female D4R, with only a strong trend toward a disruption in PPI in the
male D4R mice. Although it is not clear why AMPH appears to be less
effective in the D4R wild-type mice, there were robust effects of AMPH
in both the female D4R wild-type mice and in the male D4R knock-out mice. Although various effects of gender and genotype were found, ultimately the effects of AMPH were consistent on PPI and ASR in both
the D2R and D4R mice.
Previous reports demonstrate that the nonselective DA agonists AMPH and
apomorphine (Mansbach et al., 1988; Geyer et al., 1990), as well as the
more selective D2 agonist quinpirole (Peng et al., 1990), disrupt PPI
in rats, supporting the role of the DA D2R in the modulation of PPI.
Furthermore, the D2R selective antagonists haloperidol and raclopride
are effective in restoring an apomorphine-induced disruption in PPI
(Mansbach et al., 1988; Swerdlow et al., 1991). The present study using
genetically altered mice confirms that indeed the D2R is a necessary
part of the network of receptors that mediate the effects of AMPH on
PPI, because AMPH had no effect on PPI in mice that lacked the D2R
subtype. In both the D3R and D4R mice, PPI was disrupted by AMPH,
regardless of genotype, suggesting that neither the D3R nor the D4R is
mandatory for an indirect DA agonist to disrupt PPI. This result seems
to contradict findings that D3R agonists, including 7-OH-DPAT,
PD128907, and quinelorane, disrupt PPI in rats (Caine et al., 1995;
Bristow et al., 1996; Varty and Higgins, 1998), and selective D4R
antagonists restore apomorphine-induced disruptions in PPI (Corbin and
Heffner, 1997; Mansbach et al., 1998). There may be several
reasons for these discrepancies. One possibility is that a difference
in the dopaminergic systems between the rat and the mouse accounts for the relative receptor contributions to the modulation of PPI. A more
plausible reason might be that these compounds are not sufficiently
selective to identify subtype-specific effects. All of the "D3R
agonists" have some affinity for the D2 receptor (Seeman and Van Tol,
1994; Bowery et al., 1996). As described by Seeman and Van Tol (1994),
however, it is difficult to obtain accurate comparisons of agonist
selectivities in vitro and in vivo because of
limitations in the affinity states of receptors in cultured cells.
There are also discrepancies in the reported relative affinities of the
D4R antagonists for the D4R versus the D2R (Bristow et al., 1997b;
Mansbach et al., 1998). A related explanation for the inconsistent
findings using "selective" D4R antagonists may be that D4R
antagonism is only effective in restoring an apomorphine-induced disruption of PPI at the highest doses tested (Corbin and Heffner, 1997; Mansbach et al., 1998), which may have been acting at the D2R
(Bristow et al., 1997a).
Regardless of genotype, D2R, D3R, and D4R mutant mice displayed reduced
startle reactivity after administration of AMPH, a finding that is
consistent with other reports (Dulawa and Geyer, 1996). Thus, the
ability of AMPH to reduce startle reactivity may not depend on a DA D2
family receptor subtype. Of note is the fact that the D2R (/) mice
had normal PPI, but a reduced ASR, after receiving AMPH. This finding
lends further support for the dissociation between the effects of
dopaminergic manipulations on PPI versus the ASR indicated by previous
studies in rats. For example, 6-OHDA lesions of the nucleus accumbens
(an area rich in D2R) reduced the ability of AMPH to disrupt PPI but
did not affect the ability of AMPH to affect the ASR (Swerdlow et al., 1990). Similarly, some groups find that AMPH increases startle reactivity in rats (Davis et al., 1975; Mansbach et al., 1988; Swerdlow
et al., 1990), whereas others find no change in the ASR after AMPH
treatment (Bakshi et al., 1995; Johannson et al., 1995). It remains
unclear why AMPH would have differential effects on startle
reactivity in rats and mice, but the effects of another DA agonist,
apomorphine, on the ASR seem to depend on the strain of rat being
tested (Mansbach et al., 1988; Davis et al., 1990; Rigdon, 1990; Varty
and Higgins, 1994).
Measures of deficient PPI in animals have been used widely in studies
addressing the neurobiology of impaired sensorimotor gating in patients
with schizophrenia (Geyer et al., 1990; Swerdlow et al., 1994).
Symptomatic patients with schizophrenia or nonmedicated schizotypal
patients exhibit deficits in PPI (Braff et al., 1992; Cadenhead et al.,
1993) that appear similar to those produced by DA agonists in rodents.
As predicted by the DA hypothesis of schizophrenia, activation of the
DA system disrupts sensorimotor gating in rodents (Mansbach et al.,
1988; Dulawa and Geyer, 1996). It is widely accepted that antagonists
of the D2-like family of receptors are efficacious in the treatment of
schizophrenia (Creese et al., 1976). Indeed, the ability of an
antipsychotic drug to restore an apomorphine-induced disruption of PPI
in rats correlates with its affinity for D2 receptors (Swerdlow et al.,
1994). The present findings that the D2R plays a crucial role in the
AMPH-induced disruption of sensorimotor gating in mice provides further
support for this relationship and specifically identifies the D2R
subtype of the D2 family of receptors as being the most relevant to
this effect of an indirect DA agonist. Conversely, these findings
suggest that neither the D3R nor the D4R provide important
contributions to sensorimotor gating deficits induced by dopaminergic
activation. Antagonists at either the D3R or D4R subtypes have been
proposed as candidates for antipsychotic treatments (Sokoloff et al.,
1990; Seeman et al., 1997). To the extent that the disruption of PPI in
rodents produced by dopaminergic activation provides a predictive measure of the therapeutic actions of antipsychotic drugs (Geyer et
al., 1990; Swerdlow et al., 1994), the present observations support the
hypothesis that the D2R subtype, but not the D3R or D4R subtypes, of DA
receptors is most relevant to antipsychotic drug action.
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FOOTNOTES |
Received Jan. 14, 1999; revised March 5, 1999; accepted March 12, 1999.
This work was supported by grants from the National Alliance for
Research on Schizophrenia and Depression and the National Institute on Drug Abuse. R.J.R. was supported by predoctoral National Research Service Award Grant F31-MH12086 from the National Institute of
Mental Health (NIMH). M.G.C. is an Investigator, and M.R. is an
International Research Scholar of the Howard Hughes Medical Institute.
M.A.G. has an equity interest in San Diego Instruments, Inc. and was
supported by Research Scientist Award K05-MH01228 from NIMH. We thank
Virginia Lehmann-Masten, Darlene Giracello, and Elizabeth Lutz for
their technical assistance.
Correspondence should be addressed to Dr. Mark A. Geyer, Department of
Psychiatry, University of California at San Diego, La Jolla, CA
92093-0804.
| |
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TOP
ABSTRACT
INTRODUCTION
